UCSF Finding Offers Provocative Insight Into What Drives Cancer

In a finding that calls into question a prevailing belief about the way in which cancers develop and progress, researchers led by a UCSF scientist report that it may take only two interlocking genetic steps to cause tumors to develop.

In their study, published in the May 3 issue of Cell, the researchers focused on a protein known as c-Myc, which is produced by the c-myc oncogene. Oncogenes are a class of genes that stimulate normal cell growth but, when damaged, or "mutated," send a cell into replication overdrive, the hallmark of cancer. The c-myc oncogene is activated in most human cancers. The current study is focused on the c-Myc protein, but the researchers predict that the phenomenon they observe will be emblematic of what occurs with other oncoproteins, too.

In their study, which involved inserting a "switchable" form of the human c-Myc oncoprotein into the pancreatic cells of live mice, the scientists made three important discoveries: First, they determined that c-Myc harbors a key cancer-preventing mechanism -- the ability to cause cell death, or apoptosis. Second, they determined that thwarting this mechanism by activating another oncoprotein, known as Bcl-xL, caused full-blown cancers.

Finally, they showed that switching off the c-Myc protein triggered the collapse of robust cancerous tumors -- and the blood vessels fueling them.

"The results we saw were dramatic," says the senior author of the study, Gerard Evan, the Gerson and Barbara Bass Baker Distinguished Professor of Cancer Biology at UCSF. "Suppressing the cell-suicide pathway in c-Myc triggered the immediate growth of invasive, angiogenic tumors, while turning off c-Myc caused collapse of the tumors and rapid regression of the vasculature and invasiveness that support a metastatic tumor."

Scientists have known that c-Myc has a cell-suicide mechanism, and have presumed that it serves as a safety valve, kicked into action when c-Myc-induced cell proliferation occurred inappropriately and in the wrong tissue environment. However, they have not known how or when it functioned -- or how potent it was.

"It has been extremely difficult to demonstrate that c-Myc-induced cell death really does suppress malignancy in animals," says Evan. "Our new study is the long-awaited proof."

The finding is provocative, for during the last decade research has suggested that it takes a host of oncogenic missteps, accumulated in a multi-stage process, to prompt the panoply of events that lead to cancer. These events include uncontrolled cell proliferation; loss of ability to specialize, or "differentiate;" the development of a blood vessel system, or "angiogenesis;" and the migration and interaction of a tumor with neighboring cells and surrounding tissue.

The UCSF-led study calls this theory into question, says Evan. "Our data demonstrate that complex cancerous tumors can be induced and maintained in the body -- at least the mouse body -- by a simple combination of just two interlocking molecular lesions," he says.

"Once its lethal properties were suppressed by Bcl-xL, we could see that the c-Myc oncoprotein had the ability to orchestrate all of the other required attributes of cancerous cells, including generation of a blood supply. When c-Myc was turned off, the blood supply collapsed and all the tumors regressed."

The question, of course, is how often two such inter-linked mutations would occur.

"You have to have the right two lesions, working in combination," says Evan. "c-Myc alone drives cell growth but this is overcome by cell death. Bcl-xL alone keeps cells alive but shuts down their growth. Only when you get the two together do you get this remarkable cooperation. The chances of two such mutations occurring together are very low, and this may be the fortunate reason that cancer cells arise so rarely in our bodies."

Evidence suggests that most, perhaps all, oncogenes have some form of default valve that arrests further cell growth and limits their potential to form tumors. A next step, says Evan, will be to determine whether other proteins that make cells proliferate and that get mutated in cancer, such as the cyclin dependent kinases and the E2F transcription factors, share with the Myc protein the ability to elicit complex tumor characteristics such as angiogenesis, invasion and metastasis. However, he says, even when a tumor is driven by mutations in genes other than c-myc, it remains likely that c-Myc function will be required for tumor cell proliferation, de-differentiation, invasion and angiogenesis.

Consequently, therapeutic targeting of Myc would be expected to have profound therapeutic utility, he says. "In essence, we are trying to define the minimal mission critical targets that are needed to maintain a malignancy. Tumors acquire multiple mutations through their long histories, but not all are needed to maintain the cancer. In trying to design effective and smart therapies we can't afford to get bogged down in a history lesson about how the malignancy arose. We have to focus on what is sustaining the malignancy.

"Our data show that many of the complex characteristics of tumors that are commonly thought to have arisen through the painstaking accumulation of many different mutations can arise directly as a consequence of c-Myc activation. Once this occurs you get unrelenting cell expansion, and all the other diverse characteristics of tumors seem to come along for the ride."

If the finding bears out with other oncogenes in animal models, and later in humans, the few interdependent mutations could prove key targets for therapy, he says.

The finding builds on previous research that Evan conducted in cell culture. (Cell 69 [1]: 119-28, 3 April 1992). This earlier paper -- one of the 10 most cited papers in Molecular Biology and Genetics during the last decade -- indicated that oncoproteins such as c-Myc carry the seeds of their own destruction by triggering apotosis.

The new finding offers a possible explanation for Evan's long-standing question of why cancer is so relatively rare: "c-Myc is likely to be mutated in one or other of the hundred thousand billion cells in our bodies hundreds of times each day. If such cells immediately start to expand, we might expect cancers to be arising all the time. Cancers should be very common, when in fact they are amazingly rare. Over an entire lifetime, only one in three people develop cancer, even though each of us has trillions of cells, each of which could become a tumor cell. This means that there must be something that prevents genes like c-Myc, when they get activated, from inevitably and immediately forming cancers. The propensity of proteins like c-Myc to induce apoptosis provides a key to this puzzle. Genes like c-Myc are booby-trapped: when activated out of context, they trigger cell death and can only drive cell proliferation in the right place at the right time."

Details of the study: The researchers conducted their study in mice, specifically in the pancreatic beta cells, which produce insulin. When c-Myc was activated, the cells initially began to proliferate uncontrollably. However, the c-Myc booby trap then activated and the developing tumor mass rapidly disintegrated. Scientists have known that while c-Myc induces cell proliferation, it also has the potential to trigger cell death in cells that proliferate inappropriately and in the wrong tissue environment. However, this theoretical safety valve has never been observed before in a living tissue.

The researchers then went on to show that when they inhibited the ability of c-Myc to induce cell death (apoptosis) by introducing expression of a second oncoprotein called Bcl- xL, the proliferating cells immediately developed into a cancerous mass. Finally, however, in a finding that offers a new hope for therapy, they showed that when c-Myc was de-activated, the tumors rapidly and completely regressed.

Co-authors of the study were Stella Pelengaris of the Molecular Medicine Research Center, Department of Biological Sciences, University of Warwick, UK, and Imperial Cancer Research Fund Laboratories, UK; and Dr. Michael Khan of the Molecular Medicine Research Center, Department of Biological Sciences, University of Warwick, UK.

Evan is a member of the Daiichi Cancer Research Program at UCSF; Pelengaris was supported by the Samuel Scott of Yews Trust and Coventry General Charities.